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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`NDA 022044/S-010, S-012 and S-013
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`Merck Sharp and Dohme Corp.
`Attention: Richard J. Swanson, Ph.D.
`Director, Regulatory Affairs
`P.O. Box 1000, UG2C-50
`North Wales, PA 19454-1099
`
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`Dear Dr. Swanson:
`
`Please refer to your supplemental new drug applications (sNDAs) dated and received
`December 19, 2008 (S-010), March 31, 2009 (S-012) and November 13, 2009 (S-013), submitted
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`under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Janumet
`(sitagliptin/metformin HCl) Tablets.
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`We also acknowledge receipt of your submissions dated February 17, 2010 (S-010 and S-012)
`and December 21 and 31, 2009, and January 5, 15, 20 and 21, and February 4, 8 and 19, 2010
`(S-013).
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`Your submission of February 17, 2010 (S-010 and S-012) constitutes a complete response to our
`January 25, 2010 action letter.
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`The “Prior Approval” supplemental applications S-010 and S-012 provide for the use of Janumet
`in combination with a PPARγ agonist (S-010) and for the use of Janumet in combination with
`insulin (S-012). The “Prior Approval” supplement S-013 contains proposed safety related
`labeling changes to the Package Insert regarding the risk of pancreatitis as well as a newly
`created Medication Guide, and a proposed Risk Evaluation and Mitigation Strategy (REMS).
`The Package Insert containing the pancreatitis-related changes was approved under supplemental
`application S-011 on December 28, 2009.
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`We have completed our review of these applications, as amended. They are approved, effective
`on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling text.
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`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as
`described at http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed
`labeling (text for the package insert and the Medication Guide). For administrative purposes,
`please designate this submission, “SPL for approved NDA 022044/S-010, S-012 and S-013”.
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`
`

`

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`
` NDA 022044/S-010, S-012 and S-013
`Page 2
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`We request that the revised labeling approved today be available on your website within 10 days
`of receipt of this letter.
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and container labels as proposed in the enclosed representative carton
`and immediate container labels submitted on November 13, 2009, as soon as they are available,
`but no more than 30 days after they are printed. Please submit these labels electronically
`according to the guidance for industry titled Providing Regulatory Submissions in Electronic
`Format – Human Pharmaceutical Product Applications and Related Submissions Using the
`eCTD Specifications (October 2005). Alternatively, you may submit 12 paper copies, with 6 of
`the copies individually mounted on heavy-weight paper or similar material. For administrative
`purposes, designate this submission “Final Printed Carton and Container Labels for approved
`NDA 022044/S-013”. Approval of this submission by FDA is not required before the labeling is
`used.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`
`Section 505-1 of the FDCA authorizes FDA to require the submission of a REMS if FDA
`becomes aware of new safety information and makes a determination that such a strategy is
`necessary to ensure that the benefits of the drug outweigh the risks (section 505-1(a)).
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`Since Janumet (sitagliptin/metformin HCl) was approved on March 30, 2007, we have become
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`aware of 88 cases of pancreatitis associated with the use of sitagliptin in FDA’s Adverse Event
`Reporting System (AERS) database. These include two cases of necrotizing pancreatitis. We
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`consider this information to be “new safety information” as defined in section 505-1(b)(3) of the
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`FDCA.
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`Your proposed REMS, submitted on November 13, 2009, amended on January 5, 15 and 20, and
`February 4, 8 and 19, 2010, and appended to this letter, is approved. The REMS consists of the
`Medication Guide included with this letter and the timetable for submission of assessments of the
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`REMS.
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`Your assessment of the REMS should include an evaluation of patients’ understanding of the
`serious risks of Janumet (sitagliptin/metformin HCl).
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`The requirements for assessments of an approved REMS under section 505-1(g)(3) include, in
`section 505-1(g)(3)(B) and (C), requirements for information on the status of any postapproval
`study or clinical trial required under section 505(o) or otherwise undertaken to investigate a
`safety issue. You can satisfy these requirements in your REMS assessments by referring to
`relevant information included in the most recent annual report required under section 506B and
`21 CFR 314.81(b)(2)(vii) and including any updates to the status information since the annual
`report was prepared. Failure to comply with the REMS assessments provisions in 505-1(g)
`could result in enforcement action.
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`

`

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` NDA 022044/S-010, S-012 and S-013
`Page 3
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`We remind you that in addition to the assessments submitted according to the timetable included
`in the approved REMS, you must submit a REMS assessment and may propose a modification to
`the approved REMS when you submit a supplemental application for a new indication for use as
`described in Section 505-1(g)(2)(A) of FDCA.
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`Prominently identify submissions containing REMS assessments or proposed modifications of
`the REMS with the following wording in bold capital letters at the top of the first page of the
`submission:
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`NDA 022044 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 022044
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
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`NEW SUPPLEMENT FOR (NEW INDICATION FOR USE)
`FOR NDA 022044
`REMS ASSESSMENT
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`PROPOSED REMS MODIFICATION (if included)
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require
`holders of approved drug and biological product applications to conduct postmarketing studies
`and clinical trials for certain purposes, if FDA makes certain findings required by the statute
`(section 505(o)(3)(A)).
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`Since Janumet (sitagliptin/metformin HCl) was approved on March 30, 2007, we have become
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`aware of “new safety information” as described above.
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`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk
`of acute pancreatitis, including necrotizing forms, associated with the use of Janumet
`(sitagliptin/metformin HCl) .
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess this serious
`risk.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
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`

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`1603: A 3-month pancreatic safety study in a diabetic rodent model treated with
`sitagliptin.
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`The timetable you submitted on January 21, 2010, states that you will conduct this study
`according to the following timetable:
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`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
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`June 15, 2010
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`March 15, 2011
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`June 15, 2011
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` NDA 022044/S-010, S-012 and S-013
`Page 4
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`Submit the protocol to your IND, with a cross-reference letter to this NDA. Submit all final
`reports to your NDA. Prominently identify the submission with the following wording in bold
`capital letters at the top of the first page of the submission, as appropriate:
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`
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`• REQUIRED POSTMARKETING PROTOCOL UNDER 505(o)
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`• REQUIRED POSTMARKETING FINAL REPORT UNDER 505(o)
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`• REQUIRED POSTMARKETING CORRESPONDENCE UNDER 505(o)
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
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`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
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`FDA will consider the submission of your annual report under section 506B and 21 CFR
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`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We
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`remind you that to comply with 505(o), your annual report must also include a report on the
`status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to
`submit an annual report for studies or clinical trials required under 505(o) on the date required
`will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement
`action.
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`PROMOTIONAL MATERIALS
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`All promotional materials for your drug product that include representations about your drug
`product must be promptly revised to make it consistent with the labeling changes approved in
`this supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions to
`your promotional materials should include prominent disclosure of the important new safety
`information that appears in the revised package labeling. Within 7 days of receipt of this letter,
`submit your statement of intent to comply with 21 CFR 314.70(a)(4) to the following address or
`by facsimile at 301-847-8444:
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`
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`

`

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` NDA 022044/S-010, S-012 and S-013
`Page 5
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`In addition, as required under 21 CFR 314.81(b)(3)(i), you must submit your updated final
`promotional materials, and the package insert(s), at the time of initial dissemination or
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`publication, accompanied by a Form FDA-2253, directly to the above address. For instruction
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`on completing the Form FDA 2253, see page 2 of the Form. For more information about
`submission of promotional materials to the Division of Drug Marketing, Advertising, and
`Communications (DDMAC), see
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`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`If you issue a letter communicating important safety related information about this drug product
`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
`the letter to both this NDA and to the following address:
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`
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`MedWatch
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`Food and Drug Administration
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`5600 Fishers Lane, Room 12B05
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`Rockville, MD 20857
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
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`If you have any questions, call Mehreen Hai, Ph.D., Regulatory Project Manager, at
`(301) 796-5073.
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`Sincerely,
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` {See appended electronic signature page}
`
`Mary H. Parks, M.D.
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` Director
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`

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` NDA 022044/S-010, S-012 and S-013
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`Page 6
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`Enclosures:
`Package Insert
`Medication Guide
`REMS
`Carton and Container Labeling
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`
`
`

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`Application
`Type/Number
`--------------------
`NDA-22044
`
`Submission
`Type/Number
`--------------------
`SUPPL-13
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`NDA-22044
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`SUPPL-12
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`NDA-22044
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`SUPPL-10
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`Submitter Name
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`Product Name
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`--------------------
`MERCK AND CO
`INC
`MERCK AND CO
`INC
`MERCK AND CO
`INC
`
`------------------------------------------
`JANUMET(PHOSPHATE/METFO
`RMIN HCL FIXED DO
`JANUMET(PHOSPHATE/METFO
`RMIN HCL FIXED DO
`JANUMET(PHOSPHATE/METFO
`RMIN HCL FIXED DO
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY H PARKS
`02/26/2010
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`